Health and Genetic Ancestry Testing: Time to Bridge the Gap Andrew Smart1* , Deborah A

Smart et al. BMC Medical Genomics (2017) 10:3 DOI 10.1186/s12920-016-0240-3

DEBATE Open Access Health and genetic ancestry testing: time to bridge the gap Andrew Smart1* , Deborah A. Bolnick2 and Richard Tutton3

Abstract Background: It is becoming increasingly difficult to keep information about genetic ancestry separate from information about health, and consumers of genetic ancestry tests are becoming more aware of the potential health risks associated with particular ancestral lineages. Because some of the proposed associations have received little attention from oversight agencies and professional genetic associations, scientific developments are currently outpacing governance regimes for consumer genetic testing. Main text: We highlight the recent and unremarked upon emergence of biomedical studies linking markers of genetic ancestry to disease risks, and show that this body of scientific research is becoming part of public discourse connecting ancestry and health. For instance, data on genome-wide ancestry informative markers are being used to assess health risks, and we document over 100 biomedical research articles that propose associations between mitochondrial DNA and Y chromosome markers of genetic ancestry and a wide variety of disease risks. Taking as an example an association between coronary heart disease and British men belonging to Y chromosome haplogroup I, we show how this science was translated into mainstream and online media, and how it circulates among consumers of genetic tests for ancestry. We find wide variations in how the science is interpreted, which suggests the potential for confusion or misunderstanding. Conclusion: We recommend that stakeholders involved in creating and using estimates of genetic ancestry reconsider their policies for communicating with each other and with the public about the health implications of ancestry information. Keywords: Direct-to-consumer genetic tests, Genetic ancestry, Disease/Health risk, Regulation, Social implications, Public understanding

Background independent and distinct, little guidance is available to While genetic ancestry tests marketed to consumers do help consumers understand and interpret the reported not currently claim to provide information about disease connections between genetic ancestry and disease risk. risk, it is becoming increasingly difficult to keep infor- Consequently, when such findings circulate in the pub- mation about ancestry separate from information about lic realm, consumers learn that there may be health health. In this article, we consider the recent and unre- risks tied to their genetic ancestry even though com- marked upon growth in genetic tests and biomedical panies do not report those associations. There is there- studies linking markers of genetic ancestry to various fore potential for confusion or misunderstanding that is diseases and medical conditions. These developments problematic for both consumers and the scientific com- are becoming part of public discourse connecting ancestry munity. We argue that the various stakeholders in genetic and health, but because genetic testing companies, over- ancestry testing need to reconsider what they communi- sight agencies, and professional genetic associations cate about the health implications of ancestry information, have largely treated health and ancestry genetic tests as both to the public and to each other, in order to effectively bridge the gap that currently exists in policies and * Correspondence: [email protected] consumer guidance regarding genetic tests for ancestry 1 Department of Sociology, Bath Spa University, Newton Park, Bath BA2 9BN, and health. UK Full list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Smart et al. BMC Medical Genomics (2017) 10:3 Page 2 of 9

The gap between genetic tests for health and ancestry via media coverage of scientific studies and ancestry online discussion groups. Genetic ancestry tests were first marketed directly to This blurring of the line between genetic ancestry and consumers in 2000, for the purpose of reconstructing health accentuates the gaps that currently exist in policy genealogies and investigating personal genetic heritage. and in the available guidance for consumers because little They quickly became the most popular of all consumer attention has been given to the health implications of genetic testing services, and more than three million in- genetic ancestry testing. However, as others have noted, it dividuals have reportedly purchased these tests to date may become common for consumers to share their ances- [1, 2]. Over the last 15 years, companies [3], regulators try test results or ancestry-related estimates of disease risk [4] and professional scientific associations [5, 6] have with their physicians, expecting such information to in- treated ancestry genetic tests differently than medical or form their healthcare decisions and improve their quality health-oriented genetic tests. Tests that make health- of care [13, 14]. It is therefore crucial that we bridge these related claims or have implications for the prevention, gaps to ensure that genetic testing information is used ap- diagnosis, or treatment of disease have been subject to propriately in health-related decisions and clinical care. greater scrutiny and oversight, as regulators have sought This is especially important because most physicians lack to ensure that potentially life-changing healthcare deci- the expertise needed to interpret and contextualize the re- sions are not made on the basis of poor quality informa- sults of genetic tests: only 29% of US clinicians surveyed tion or with a lack of appropriate medical knowledge, rate their knowledge of genetics as excellent, very good, or advice, and support [7]. Genetic ancestry tests have re- good [15], and less than a third of the physicians surveyed ceived less attention from legislators, policy makers and in five European countries were confident or very regulatory agencies because they are not marketed expli- confident in their ability to carry out basic medical genetic citly for disease diagnosis, treatment, or prevention, and tasks [16]. Given these findings, there is a real risk that have thus been seen as more “recreational”, less conse- consumers or their physicians could make problematic quential, and less ethically problematic. This differenti- and potentially irreversible healthcare decisions based on ation between ancestry and health genetic testing has inaccurate, misleading, or misinterpreted genetic testing seemed appropriate because the two types of tests have results. Genetic ancestry information has been misinter- had such different applications. preted or over-interpreted in the past [17–19], and it has However, recent developments demonstrate that the been used in ways that reach far beyond the intended or boundary between ancestry-related and health-related anticipated scientific applications — for example, in con- genetic testing is more porous than previously suggested troversial attempts to use genetic ancestry tests to support [8], and it is being transgressed in a variety of ways. Native American tribal membership claims [20] and to When genetic testing company 23andMe suspended its infer nationality in asylum cases [21]. ‘health reports’ in 2013, following a warning from the Thus, it is critical that we recognize and address the US Food and Drug Administration (FDA), it continued increasingly porous boundary between genetic tests for to provide customers with ancestry information and ancestry and health because (1) genetic ancestry tests can their raw genetic data [9, 10]. With these ancestry testing provide information that has consequences for health data, consumers could still obtain an assessment of their decision-making, (2) test-takers may have unrealistic health risks using independent online ‘interpretation-only’ expectations about the scientific and medical certainties services for as little as $5 [11]. More explicit links between offered by the tests they have purchased, (3) many physi- genetic ancestry and health are evident in 23andMe’sre- cians are not prepared to interpret and apply the genetic launched Health + Ancestry Service, which was approved test results that their patients may bring into the clinic, by the FDA as a ‘medical device’ and provides both ances- and (4) better guidance for consumers is needed to ensure try and health information. This service directly connects that health-related information from genetic ancestry tests ancestry to health in its ‘wellness’ reports for traits like lac- is interpreted and applied in valid ways. This is especially tose intolerance and in its ‘carrier status’ reports for med- important because, as we show in the next section, scien- ical conditions like cystic fibrosis and sickle cell tific and biomedical studies have been drawing ever more anemia, as both link risk estimates to named racial/ connections between ancestry and health, and there is evi- ethnic groups. At least one other leading genetic test- dence that these connections are beginning to affect con- ing company (Ancestry.com) is in discussions with the sumer interpretations of their genetic ancestry test results. FDA about expanding its service to include similar carrier status reports [12]. Furthermore, as we show in Mounting evidence of connections between this article, even when genetic ancestry tests report genetic ancestry and disease risk only an individual’s ancestry, consumers can become Genetic ancestry plays an important role in contemporary aware of possible health risks tied to their genetic biomedical science. Medical genetic studies, for instance, Smart et al. BMC Medical Genomics (2017) 10:3 Page 3 of 9

commonly use ancestry inferences derived from auto- studies, many publications present possible associations somal markers (typically single nucleotide polymorphisms between mtDNA/Y haplogroups and disease risk, and or “ancestry informative markers”)tocontrolforpopula- consumers are becoming aware of these reports as they tion stratification, a practice that underpins the now rou- garner media attention and enter public discourse. tine reporting of population-specific or ancestry-specific In 2012, for example, a study published in The Lancet estimates of disease risks and drug response in genetic found that British men belonging to Y chromosome epidemiology [13, 22]. Far less attention has been given to haplogroup I have a 50% higher age-adjusted risk of the fact that studies using uniparental genetic markers coronary artery disease (CAD) than other British men, have uncovered connections between ancestry and health. with haplogroup I being the most significant predictor These tests have been a mainstay of the direct-to-consumer of CAD after HDL cholesterol and lipid-lowering treat- ancestry-testing marketplace, but have been widely con- ment [24]. This finding was widely reported by the sidered to have little biomedical value [13]. media in the UK, US, and Australia, under headlines Over the last decade, hundreds of biomedical studies about heart disease risk being inherited along paternal have been published that suggest that certain mito- lines (Tables 1 and 2). This coverage demonstrated the chondrial DNA (mtDNA) and Y chromosome variants potential for raised consumer expectations about the (and the haplogroups defined by those variants) are value of genetic ancestry information to health, and the associated with an increased risk of disease and other future possibilities of acting on that information. One health complications [23]. These variants and hap- article, for example, suggested that: “when a screening test logroups have been linked to a diverse array of common is developed to find those Y chromosome gene clusters diseases and medical conditions, including coronary artery and researchers have a better understanding of how they disease, myocardial infarction, ischaemic stroke, heart act, it may be possible to protect some [unlucky men] transplant complications, Leber hereditary optic neuro- from having heart attacks.” [29] The UK National Health pathy, advanced age-related macular degeneration, Service added an extensive discussion of ancestral hap- hearing loss, osteoarthritis, osteoporosis, multiple scler- logroups and CAD to their patient information website, osis, Alzheimer’sandParkinson’s disease, complications NHS Choices, after the study was published — albeit to from type 2 diabetes (especially retinopathy, neuro- argue that this information was not of immediate use for pathy, nephropathy, and renal failure), several types of tackling CAD in the UK because, among other reasons, cancer (breast, thyroid, pancreatic, esophageal, colorec- “men are unlikely to know their specific haplogroup, so tal, prostate, renal, and lung cancer), and the rate of are unlikely to know whether they may be at increased AIDS progression in HIV patients (an additional table risk of CAD” [30]. Ancestry testing consumers dis- shows examples of associations discussed in the bio- cussed this Lancet study (along with other reports of medical literature [see Additional file 1]). The exact haplogroup-associated disease susceptibilities) in online causes of these associations are not always clear, but it forums (in threads entitled, for example, “Medical con- is thought that the associated genetic variants alter the ditions associated with Y-chromosome haplogroups” expression of key gene pathways [24] or, in the case of and “Do not read if you are a hypochondriac…”), and a mtDNA, contribute to the development and progression Principal Scientist at 23andMe blogged about the study, of disease by affecting energy metabolism and important expressing skepticism about the study’s conclusions and cellular processes, including ATP synthesis, reactive oxy- offering an alternative analysis using his company’sdata gen species (ROS) production, oxygen consumption effi- (Table 3). Thus, by following the circulation of this ciency, calcium signaling, and apoptosis [25–27]. study in public domains, we can see variation in how It is important to note that the quality of studies the study was understood, disagreement over the ro- reporting associations between mtDNA/Y chromosome bustness of its conclusions, and a lack of clarity about haplogroups and disease susceptibility is quite variable. the significance of genetic ancestry markers like hap- Some haplogroup-disease associations are supported by logroups to health. multiple independent studies with rigorous statistical While similar observations can be made about studies designs, but many others are not. The biomedical litera- of autosomal or genome-wide markers and disease risk, ture includes a large number of studies that suffer from we have focused here on uniparental genetic markers be- small sample sizes, inappropriate controls for population cause mtDNA and Y chromosome tests are the two stratification, and/or problematic statistics (for example, types of genetic ancestry tests that companies, policy- P-values that have not been corrected for multiple com- makers, regulators, and professional scientific associa- parisons), so some of the reported haplogroup-disease tions have invariably treated as less relevant to health. associations are almost certainly false positives. Other However, as we have shown, there is public interest in researchers have also drawn attention to these problems the extensive biomedical literature investigating the as- [23, 28]. However, regardless of the quality of these sociations between mtDNA/Y chromosome haplogroups Smart Table 1 Coverage of Charchar et al. [24] in mainstream news media

Outlet Author Date Headline Section URL Quoted Genomics Medical BMC al. et BBC News Online (UK) Michelle Roberts 09/02/12 Men can inherit a form of Health www.bbc.co.uk/news/health- Dr Maciej Tomaszewski heart disease from father via 16931585 (University of Leicester); Dr Hélène Y chromosome Wilson (British Heart Foundation) The Independent (UK) Jeremy Laurance 09/02/12 Male gene increases risk of Health www.independent.co.uk/life-style/ Dr Maciej Tomaszewski hereditary heart disease for health-and-families/ health-news/ (University of Leicester); one in five male-gene-increases-risk-of-heredi- Dr Virginia M. Miller (Mayo Clinic) tary-heart-disease-for-one-in-five- 6676537.html

The Daily Telegraph Rebecca Smith 09/02/12 One in five men have DNA Health www.telegraph.co.uk/health/ Dr Hélène Wilson (British Heart (2017)10:3 (UK) that puts them at greater risk healthnews/9068859/One-in-five- Foundation); Dr Maciej Tomaszewski of a heart attack: research men-have-DNA-that-puts-them-at- (University of Leicester); greater-risk-of-a-heart-attack- Dr Virginia M. Miller (Mayo Clinic) research.html The Daily Mail (UK) Sadie Whitelocks 09/02/12 Men can inherit higher risk Health www.dailymail.co.uk/health/article- Dr Hélène Wilson (British Heart of heart attack from father - 2098314/Fathers-common-gene- Foundation); Dr Maciej Tomaszewski and can pass danger on to variant-50-cent-higher-risk-heart- (University of Leicester) their sons disease–pass-sons.html The Daily Mirror (UK) Lachlan MacKinnon 09/02/12 Close to men’s hearts: Y Technology and science www.mirror.co.uk/news/technology- Dr Hélène Wilson (British Heart chromosome link to coronary science/science/close-to-mens- Foundation); Dr Maciej Tomaszewski risk hearts-y-chromosome-678644 (University of Leicester) Time (USA) Alexandra Sifferlin 09/02/12 Like Father like Son? Y Heart Disease healthland.time.com/2012/02/09/like- Scientific American Dr Maciej Chromosome Linked to father-like-son-y-chromosome-linked- Tomaszewski (University of Leicester) Heart Disease to-heart-disease/ CBS News (USA) Brenda Goodman 09/02/12 Some men may inherit a News http://www.cbsnews.com/news/ Lisa Bloomer (University of Leicester); higher risk of heart disease some-men-may-inherit-a-higher-risk- Dr Virginia M. Miller (Mayo Clinic) from dad of-heart-disease-from-dad/ The New York Times Gina Kolata 08/02/12 Male Genes May Explain Health www.nytimes.com/2012/02/09/ Dr Virginia M. Miller (Mayo Clinic); (USA) Higher Heart Disease Risk health/research/heart-disease-risk- Dr Sekar Kathiresan (Massachusetts may-be-tied-to-y- General Hospital); Dr. Daniel J. Rader chromosome.html?_r=0 (University of Pennsylvania) Scientific American Katherine Haron 08/02/12 Y Chromosome Can Raise Blogs http://blogs.scientificamerican.com/ Prof F Charchar (University of (USA) Courage Heart Disease Risk by 50% observations/2012/02/08/y- Ballarat); Dr Virginia M. Miller chromosome-can-raise-heart-disease- (Mayo Clinic) risk-by-50-percent/ Forbes (USA) Larry Husten 09/02/12 The Y Chromosome May Pharma and Healthcare http://www.forbes.com/sites/ The Lancet paper; Dr Virginia M. Explain Why Men Have larryhusten/2012/02/09/the-y- Miller (Mayo Clinic) Earlier Coronary Disease chromosome-may-explain-why-men- have-earlier-coronary-disease/ ae4o 9 of 4 Page Table 1 Coverage of Charchar et al. [24] in mainstream news media (Continued) Smart The Age (Australia) Deb Anderson 27/03/12 Does the Y chromosome Education Prof F Charchar (University of Ballarat) ta.BCMdclGenomics Medical BMC al. et influence men’s health? The Chronicle (Australia) Tom McIlroy 13/02/12 UB releases heart disease News http://www.thecourier.com.au/story/ Prof F Charchar (University of research 62162/ub-releases-heart-disease- Ballarat); Dr Hélène Wilson (British research/ Heart Foundation) International Business Lawrence Villamar 10/02/12 Heart Disease Risks Linked to Articles Prof F Charchar (University of Times (Australia) Genes in Men: study Ballarat) The Times of India Kounteya Sinha 10/02/12 Sons can inherit heart disease India http://timesofindia.indiatimes.com/ The Lancet paper; Dr Pramod Kumar (India) from dad: Study india/Sons-can-inherit-heart-disease- (Fortis Hospital); Dr Virginia M. Miller from-dad-Study/articleshow/ (Mayo Clinic) (2017)10:3 11829916.cms ae5o 9 of 5 Page Smart ta.BCMdclGenomics Medical BMC al. et

Table 2 Coverage of Charchar et al. [24] in online sources of medical news Site Author Date Headline URL Quoted NHS Choices 09/02/12 One in five men ‘carries heart risk gene’ www.nhs.uk/news/2012/02February/Pages/ BBC News (2017)10:3 y-chromosome-heart-disease-risk.aspx Medical News Today Jospeh Nordqvist 09/02/12 Male Gene Linked To Coronary Artery www.medicalnewstoday.com/articles/ The Lancet paper; Dr Virginia M. Disease Risk 241441.php Miller (Mayo Clinic) WebMD Brenda Goodman 08/02/12 Some Men May Inherit a Higher Risk of www.webmd.com/heart-disease/news/ Lisa Bloomer (University of Leicester); Heart Disease From Dad 20120208/some-men-may-inherit-higher-risk- Dr Virginia M. Miller (Mayo Clinic) heart-disease-from-dad Medscape Lisa Nainggolan 10/02/12 Like Father, Like Son: Y-Chromosome http://webcache.googleusercontent.com/ Lisa Bloomer (University of Leicester); Variant May Explain CAD search?q=cache:RhYvNynICn4J: Dr Virginia M. Miller (Mayo Clinic); Dr www.medscape.com/viewarticle/758437 Sekar Kathiresan (Massachusetts +&cd=1&hl=en&ct=clnk&gl=uk General Hospital) News Medical AnayaMandal 12/02/12 Y chromosome may be the link that passes www.news-medical.net/news/20120 212/Y- The Lancet paper; Dr Sekar heart disease risk from father to son chromosome-may-be-the-link-that-passes- Kathiresan (Massachusetts General heart-disease-risk-from-father-to-son.aspx Hospital); Dr Virginia M. Miller (Mayo Clinic) The Naked Scientist Kat Arney 12/02/12 Y Chromosome yields heart disease clues www.thenakedscientists.com/HTML/news/ news/2485/ MyDr 09/02/12 Heart disease risk passed from father to son Dr Virginia M. Miller (Mayo Clinic) Cure Talk Priya Menon undated Coronary Artery Disease Linked To Y trialx.com/curetalk/2012/03/coronary-artery- Chromosome: Study By Fadi J. Charchar disease-linked-to-y-chromosome-study-by- fadi-j-charchar/ Men’s Health 09/02/12 Y chromosome may increase risk of coronary www.drharryfisch.com/y-chromosome-may- artery disease increase-risk-of-coronary-artery-disease/ drholdright.co.uk 02/12 The Y male sex chromosome and risk of heart http://www.drholdright.co.uk/ disease dynamicpage.php?pg=news&pageid=OTk= ae6o 9 of 6 Page Smart ta.BCMdclGenomics Medical BMC al. et

Table 3 Coverage linking haplogroups and health online in blogs and forums Site Author Date Headline Type URL Includes Charchar et al. (2012) [24] 23andMe Dave Hinds 04/04/12 Second Opinion: Haplogroup I blog blog.23andme.com/news/second-opinion- Yes Likely Not Linked to Heart haplogroup-i-likely-not-linked-to-heart- (2017)10:3 Disease disease/ Improving Population Health David A. Kindig 07/10/12 Are Male Genetic Health blog www.improvingpopulationhealth.org/blog/ Yes Differences Disparities or 2012/07/are-male-genetic-health-differences- Inequities disparities-or-inequities.html Dienekes Anthropology Blog 09/02/12 Y-chromosomes and coronary blog dienekes.blogspot.co.uk/2012/02/y- Yes artery disease in Britain chromosomes-and-coronary-artery.html Fight Aging 05/11/13 Those Lucky Haplogroup H blog www.fightaging.org/archives/2013/11/those- No Bearers lucky-haplogroup-h-bearers.php Mathilda’s Anthropolgy Blog 03/11/08 Mitochondrial DNA and survival blog mathildasanthropologyblog.wordpress.com/ No after sepsis 2008/11/03/mitochondrial-dna-and-survival- after-sepsis/ Eupedia 28/01/09 – 23/09/13 Medical conditions associated forum www.eupedia.com/forum/threads/25199- Yes with Y-chromosome haplogroups Medical-conditions-associated-with-Y- chromosome-haplogroups familytreeDNA 09/02/12 – 10/02/12 Do not read if you are a forum forums.familytreedna.com/ Yes hypochondriac… showthread.php?t = 30303&highlight = haplogroup + health + risk Rootschat 22/05/13 – 01/06/13 Utter Confusion: please help me forum www.rootschat.com/forum/ Yes (via ref to Hinds blog) choose DNA test index.php?topic=647807.54 Eupedia 26/07/07 – 26/04/14 Medical conditions and risk forum www.eupedia.com/forum/threads/24801- No factors associated with mtDNA Medical-conditions-and-risk-factors- haplogroups associated-with-mtDNA-haplogroups Zetaboards 12/01/13 – 12/01/13 Examples of diseases associated forum s1.zetaboards.com/anthroscape/topic/ No with a haplogroup 5045507/1/ WorldFamilies 14/06/11 – 20/03/12 At last some FGS-s for R0a2 from forum www.worldfamilies.net/forum/ No Tuscany and The Marche index.php?topic=9937.0 ae7o 9 of 7 Page Smart et al. BMC Medical Genomics (2017) 10:3 Page 8 of 9

and disease, and some consumers of genetic ancestry developed by professional associations like the American tests are already trying to understand how their an- Society of Human Genetics (ASHG)? cestry is relevant to their health and disease prognosis To help address the issues raised here, we make five in light of these research findings. Other consumers recommendations for stakeholders in consumer genetic are also likely to encounter the results of these bio- testing to consider: medical studies in the popular press, in online forums, in literature from their healthcare provider, or (1) The ASHG or another respected professional in well-known medical journals, and they too may genetics society should organize a roundtable grapple with the possible health implications of their to bring the various stakeholders together to genetic ancestry test results. Therefore, even when produce authoritative guidance that will inform genetic ancestry tests report only an individual’san- and benefit consumers, and help create a set of cestral lineage or uniparental haplogroup, consumers standards for the industry to follow. This guidance can become aware of the possible relationship with should make clear what we can and cannot genetic health risks because scientists have linked know from genetic ancestry testing, and provide haplogroup ancestry to health outcomes. guidance regarding the accuracy and reliability of associations between genetic markers and health risks. Industry representatives, consumer advocates, Conclusions policy and legal advisors, biomedical researchers, Like the repurposing of genome-wide ancestry test data social scientists, and regulators should all be to assess health risks, and like the use of autosomal involved in drafting this guidance. genetic markers in genetic epidemiology to identify (2) Consumer advocates, scientific organizations, population-specific disease risks and drug response, the companies, science journalists, and government reported associations between uniparentally-inherited agencies should play a role in making this haplogroupsandvariousdiseasesrepresentanother information available to consumers. blurring of the line between genetic information on (3) Genetic ancestry testing companies should health and ancestry. Developments in scientific know- report only associations between genetic ledge and commercial practice appear to be outpacing markers and diseases/medical conditions that the current oversight and governance regimes that have been scientifically validated. They should largely treat genetic tests for ancestry and health as sep- also provide information about the limitations of arate and distinct. their tests (as 23andMe now does as part of their We therefore suggest that it is time for the various ‘carrier status’ and ‘wellness’ reports; [31]) and stakeholders in genetic ancestry testing to reconsider include information about how to interpret the what they communicate about the health implications of connections between ancestry and health among ancestry information, both to the public and to each their FAQs. other. This will require considering some difficult ques- (4) Medical schools and continuing medical education tions. For example, can and should consumer genetic (CME) programs should discuss the potential health testing companies take responsibility for the ways in implications of genetic ancestry information so that which test-takers connect ancestry test results with other physicians can help their patients to interpret and publicly available information? Can and should genetic contextualize their genetic testing results. testing companies, alongside scientific associations and (5) Policy-makers and government agencies may consumer advocates, provide guidance to consumers wish to reconsider current oversight regimes for about the accuracy and reliability of the various postu- direct-to-consumer genetic testing in light of the lated associations between haplogroups (or other genetic increasingly porous boundaries between tests for markers) and health risks? How can those who commu- health and ancestry. nicate about the relevant science (scientific researchers, journal editors, science journalists, genetic testing Our recommendations are aimed at encouraging companies, consumer advocates, policy advisors, etc.) novel and timely interventions into ongoing debates achieve maximum clarity regarding the potential health about direct-to-consumer genetic tests, especially implications of genetic ancestry (or the lack of them), since the US FDA, European Commission, ASHG, and and make effective use of the published critiques of the high-profile ancestry testing companies are all consid- putative links between uniparental haplogroups and ering scientific, ethical, and regulatory issues regarding health risks [23, 28]? Should there be any changes to health-related genetic testing. Now is the time to start policies governing the regulation or oversight of con- bridging the gap in our current approaches to health sumer genetic testing, or additions to guidelines being and ancestry genetic testing. Smart et al. BMC Medical Genomics (2017) 10:3 Page 9 of 9

Additional file 10. Seon-Hee Y, Chung Y-J. Reflections on the US FDA’s Warning on Direct-to- Consumer Genetic Testing. Genomics Inform. 2014;12(4):151–5. doi:10.5808/ GI.2014.12.4.151. Additional file 1: Examples of associations between mitochondrial DNA 11. Regalado A. How a wiki is keeping direct-to-consumer genetics alive. MIT (mtDNA) or Y chromosome variants and diseases/medical traits discussed technology review. 2014. Available: www.technologyreview.com/ in the biomedical literature. Description of data: an extensive list of published featuredstory/531461. associations between mitochondrial DNA (mtDNA) or Y chromosome variants 12. Duhaime-Ross A. Ancestry.com is talking to the FDA about using DNA to and diseases/medical traits. Organised by disease/medical traits, and including: estimate people’s risk of disease. The Verge. 2015. Available: http://www. mtDNA or Y Chromosome Variant; Proposed Association (or Lack of theverge.com/2015/10/12/9487685/ancestry-com-dna-test-kit-disease-risk-fda. Association); Study Location; and Reference. (DOCX 58 kb) 13. Royal C, et al. Inferring genetic ancestry: opportunities, challenges, and implications. Am J Hum Genet. 2010;86:661–73. Abbreviations 14. Cherkas L, et al. A survey of UK public interest in internet-based personal ASHG: American Society of Human Genetics; CAD: Coronary artery disease; genome testing. PLoS One. 2010;5(10):e13473. CME: Continuing medical education; FDA: Food and Drug Administration; 15. Bonham V, et al. Physicians’ knowledge, beliefs, and use of race and human mtDNA: Mitochondrial DNA; PGS: Personal genome service; ROS: Reactive genetic variation: new measures and insights. BMC Health Serv Res. 2014;14:456. oxygen species 16. Nippert I, et al. 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Department of diseases. Mitochondrion. 2007;7:29e38. Sociology, Lancaster University, Bowland North, Bailrigg LA1 4YN, UK. 29. Kolata G. Male genes may explain higher heart disease risk. The New York Times. 2012. Available: http://www.nytimes.com/2012/02/09/health/ Received: 30 March 2016 Accepted: 21 December 2016 research/heart-disease-risk-may-be-tied-to-y-chromosome.html. 30. Choices NHS. One in five men ‘carries heart risk gene’. 2012. Available: www. nhs.uk/news/2012/02February/Pages/y-chromosome-heart-disease-risk.aspx. References 31. 23andMe. Learn how your DNA may affect your health. 2016. Available: — 1. Kaiser J. Who has your DNA or wants it. Science. 2015;349:1475. www.23andme.com/service/. 2. Wells S. Paper presented at the International Conference for Genetic Genealogy. 2014. 3. Wagner J, et al. Tilting at windmills no longer: a data-driven discussion of DTC DNA ancestry tests. Genet Med. 2012;14:586–93. 4. Kalokairinou L, et al. Changes on the horizon for consumer genomics in the EU. Science. 2014;346:296–8. doi:10.1126/science.1256396. 5. Hudson K, et al. ASHG Statement on Direct-to-Consumer (DTC) Genetic Testing in the United States. Am Soc Hum Genet. 2007;81:635–7. 6. The American Society of Human Genetics. ASHG Ancestry Testing Statement and Recommendations: guidelines for Understanding the issues and implications involved. 2008. Available: www.ashg.org/pages/policy_ statements.shtml. 7. National Human Genome Research Institute. Regulation of genetic tests. 2014. Available: www.genome.gov/10002335. 8. Lee S, et al. The illusive gold standard in genetic ancestry testing. Science. 2009;325:38–9. 9. U.S. Food and Drug Administration. Warning letter: 23andMe, Inc. 2013. Available: www.fda.gov/iceci/enforcementactions/warningletters/2013/ ucm376296.htm. Additional File 1. Examples of associations between mitochondrial DNA (mtDNA) or Y chromosome variants and diseases/medical traits discussed in the biomedical literature.

Note: Published associations were included regardless of the quality of statistical analysis or the robustness of the reported association. Some of the associations listed here are likely false positives. This is not a comprehensive listing of all relevant studies and does not include all reported associations.

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Longevity mtDNA haplogroup D4 longevity China X. Y. Cai, et al., Association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population. PloS ONE 4, e6423 (2009), 10.1371/journal.pone.0006423. mtDNA haplogroups M9, N9, reduced longevity China X. Y. Cai, et al., Association of mitochondrial DNA haplogroups with exceptional B4a longevity in a Chinese population. PloS ONE 4, e6423 (2009), 10.1371/journal.pone.0006423. mtDNA 150T longevity Costa Rica L. Castri et al., Mitochondrial polymorphisms associated with differential longevity do not impact lifetime-reproductive success. Am J Hum Biol 23, 225-227 (2011).

mtDNA 5178A in haplogroup reduced longevity Costa Rica L. Castri et al., Mitochondrial polymorphisms associated with differential longevity do D not impact lifetime-reproductive success. Am J Hum Biol 23, 225-227 (2011).

mtDNA haplogroups D4a, D5, longevity Japan, Korea Y. Nishigaki, N. Fuku, M. Tanaka, Mitochondrial haplogroups associated with lifestyle- D4b2b related diseases and longevity in the Japanese population. Geriatr Gerontol Int 10 Suppl 1, S221-235 (2010). mtDNA haplogroup F longevity China J. Feng et al., Association of mtDNA haplogroup F with healthy longevity in the female Chuang population, China. Exp Gerontol 46, 987-993 (2011).

mtDNA 150T no association with China H. Pan et al., Absence of association between mitochondrial DNA C150T longevity polymorphism and longevity in a Han Chinese population. Exp Gerontol 46, 511-515 (2011). mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Longevity (cont.) mtDNA haplogroups no association with Spain T. Pinos et al., Are mitochondrial haplogroups associated with extreme longevity? A longevity study on a Spanish cohort. Age (Dordr) 34, 227-233 (2012). mtDNA haplogroup X successful aging USA M. D. Courtenay et al., Mitochondrial haplogroup X is associated with successful aging in the Amish. Hum Genet 131, 201-208 (2012). mtDNA haplogroup J less successful aging USA M. D. Courtenay et al., Mitochondrial haplogroup X is associated with successful aging in the Amish. Hum Genet 131, 201-208 (2012). mtDNA 150T, 73G longevity Turkey O. Guney et al., Mitochondrial DNA polymorphisms associated with longevity in the Turkish population. Mitochondrion 17, 7-13 (2014). mtDNA haplogroup D4b2 and longevity Japan N. Fuku et al., The mitochondrial-derived peptide MOTS-c: a player in exceptional 1382C longevity? Aging Cell 14, 921-923 (2015). mtDNA haplogroups no association with China Y.-H. He et al., Mitochondrial DNA plays an equal role in influencing female and male longevity longevity in centenarians. Exp Geront 83, 94-96 (2016). mtDNA haplogroup M9 reduced longevity China L. Li et al., Mitochondrial genomes and exceptional longevity in a Chinese population: the Rugao longevity study. Age 37, 14 (2015). mtDNA haplogroups A4h, longevity China L. Li et al., Mitochondrial genomes and exceptional longevity in a Chinese population: R11a1a1a the Rugao longevity study. Age 37, 14 (2015). mtDNA haplogroup C reduced longevity Costa Rica L. Castri et al., A mitochondrial haplogroup is associated with decreased longevity in a historic New World population. Hum Biol 86, 251-259 (2014).

Cancer mtDNA 239C, 263G, 16207T, breast cancer Poland A. M. Czarnecka et al, Mitochondrial genotype and breast cancer predisposition. Oncol haplogroup I Rep 24, 1521-1534 (2010). mtDNA 73G, 150T, 16183C, reduced risk of breast Poland A. M. Czarnecka et al, Mitochondrial genotype and breast cancer predisposition. Oncol 16189C, 16223T, 16362C cancer Rep 24, 1521-1534 (2010). mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Cancer (cont.) linked mtDNA 16183C, malignant melanoma Middle Europe S. Ebner et al., Mitochondrial haplogroups, control region polymorphisms and 16189C, 16192T, 16270T, malignant melanoma: a study in middle European Caucasians. PLoS One 6, e27192 195T (2011), 10.1371/journal.pone.0027192. mtDNA haplogroups M, D5 breast cancer China H. Fang et al., Cancer type-specific modulation of mitochondrial haplogroups in breast, colorectal and thyroid cancer. BMC Cancer 10, 421 (2010). mtDNA haplogroup D4a thyroid cancer China H. Fang et al., Cancer type-specific modulation of mitochondrial haplogroups in breast, colorectal and thyroid cancer. BMC Cancer 10, 421 (2010). mtDNA haplogroup Uk vulvar squamous cell Poland A. Klemba et al., Mitochondrial genotype in vulvar carcinoma - cuckoo in the nest. J carcinoma Biomed Sci 17, 73 (2010). mtDNA haplogroup H reduced risk of vulvar Poland A. Klemba et al., Mitochondrial genotype in vulvar carcinoma - cuckoo in the nest. J squamous cell carcinoma Biomed Sci 17, 73 (2010). various rare mtDNA variants pancreatic cancer USA E. T. Lam et al., Mitochondrial DNA sequence variation and risk of pancreatic cancer. Cancer Res 72, 686-695 (2012). mtDNA haplogroup D esophageal cancer China X. Y. Li et al., Association of mitochondrial haplogroup D and risk of esophageal (especially D4a, D5) cancer in Taihang Mountain and Chaoshan areas in China. Mitochondrion 11, 27-32 (2011). mtDNA haplogroup U prostate cancer USA L. M. Booker et al, North American white mitochondrial haplogroups in prostate and renal cancer. J Urol 175, 468-472 (2006). mtDNA haplogroup U no association with Middle Europe E. E. Mueller et al., Mitochondrial haplogroups and control region polymorphisms are prostate cancer not associated with prostate cancer in Middle European Caucasians. PLoS One 4, e6370 (2009), 10.1371/journal.pone.0006370. mtDNA haplogroup M breast cancer China L. Shen et al., Evaluating mitochondrial DNA in cancer occurrence and development. Ann N Y Acad Sci 1201, 26-33 (2010).

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Cancer (cont.) mtDNA haplogroup M5 breast cancer India N. R. Tipirisetti et al., Mitochondrial genome variations in advanced stage breast cancer: a case-control study. Mitochondrion 13, 372-378 (2013). mtDNA 752A, 1440A, 4770A colorectal cancer Scotland E. Theodoratou et al., Association between common mtDNA variants and all-cause or colorectal cancer mortality. Carcinogenesis 31, 296-301 (2010). mtDNA haplogroups D, F reduced risk of lung China S. Zheng et al., Association of mitochondrial DNA variations with lung cancer risk in a cancer Han Chinese population from southwestern China. PLoS One 7, e31322 (2012), 10.1371/journal.pone.0031322. mtDNA haplogroups G, M7 lung cancer China S. Zheng et al., Association of mitochondrial DNA variations with lung cancer risk in a Han Chinese population from southwestern China. PLoS One 7, e31322 (2012), 10.1371/journal.pone.0031322. mtDNA haplogroup JT myelodysplastic USA J. N. Poynter et al., Association between mitochondrial DNA haplogroup and syndromes myelodysplastic syndromes. Genes Chromosomes Cancer 55, 9 (2016), 10.1002/gcc.22370. mtDNA haplogroups no association with Colombia D. Cano et al., Mitochondrial DNA haplogroups and susceptibility to prostate cancer in prostate cancer a colombian population. ISRN Oncol. 530675 (2014), 10.1155/2014/530675.

mtDNA no association with USA E. E. Giorgi et al., No Association between the Mitochondrial Genome and Prostate prostate cancer Cancer Risk: The Multiethnic Cohort. Cancer Epidemiol Biomarkers Prev. 25, 6 (2016), 10.1158/1055-9965. mtDNA haplogroup T colorectal cancer USA Y. Li et al., Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort. PLoS One 10, e0136796 (2015), 10.1371/journal.pone.0136796. mtDNA haplogroup H breast cancer Uruguay C. Bonilla et al, Breast cancer risk and genetic ancestry: a case-control study in Uruguay. BMC Womens Health. 15, 11 (2015) 10.1186/s12905-015-0171-8.

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Cancer (cont.) mtDNA haplogroups R9, F1 nasopharyngeal carcinoma China S. P. Hu, J. P. Du, D. R. Li, Y. G. Yao, Mitochondrial DNA haplogroup confers genetic susceptibility to nasopharyngeal carcinoma in Chaoshanese from Guangdong, China. PLoS One 9, e87795 (2014), 10.1371/journal.pone.0087795.

Coronary Conditions mtDNA haplogroups N9b, M7c reduced risk of myocardial Japan, Korea Y. Nishigaki, N. Fuku, M. Tanaka, Mitochondrial haplogroups associated with lifestyle- infarction related diseases and longevity in the Japanese population. Geriatr Gerontol Int 10 Suppl 1, S221-235 (2010). mtDNA haplogroup G1 myocardial infarction Japan, Korea Y. Nishigaki, N. Fuku, M. Tanaka, Mitochondrial haplogroups associated with lifestyle- related diseases and longevity in the Japanese population. Geriatr Gerontol Int 10 Suppl 1, S221-235 (2010). mtDNA 16189C coronary artery disease & Saudi Arabia K. K. Abu-Amero et a.l, The mitochondrial DNA variant 16189T>C Is associated with myocardial infarction coronary artery disease and myocardial infarction in Saudi Arabs. Genet Test Mol Bioma 14, 43-47 (2010). mtDNA haplogroup H reduced risk of left Russia S. V. Buikin, M. V. Golubenko, V. P. Puzyrev, Genes for mitochondria in arterial ventricular hypertrophy hypertension and left ventricular hypertrophy. Mol Biol 44, 23-27 (2010).

mtDNA haplogroup T left ventricular Russia S. V. Buikin, M. V. Golubenko, V. P. Puzyrev, Genes for mitochondria in arterial hypertrophy hypertension and left ventricular hypertrophy. Mol Biol 44, 23-27 (2010).

Y chromosome haplogroup I coronary artery disease UK F. J. Charchar et al., Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet 379, 915-922 (2012). mtDNA haplogroup K reduced risk of transient UK P. F. Chinnery et al., Mitochondrial DNA haplogroups and risk of transient ischaemic ischaemic attack, & attack and ischaemic stroke: a genetic association study. Lancet Neurol 9, 498-503 ischaemic stroke (2010).

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Coronary Conditions (cont.) mtDNA haplogroup H end-stage heart failure Europe M. E. Gallardo et al., Mitochondrial haplogroups associated with end-stage heart failure and coronary allograft vasculopathy in heart transplant patients. Eur Heart J 33, 346- 353 (2012). mtDNA haplogroup Uk cardiac allograft Europe M. E. Gallardo et al., Mitochondrial haplogroups associated with end-stage heart failure vasculopathy and coronary allograft vasculopathy in heart transplant patients. Eur Heart J 33, 346- 353 (2012). mtDNA haplogroup W coronary artery disease Lebanon M. Haber et al., mtDNA lineages reveal coronary artery disease-associated structures in the Lebanese population. Ann Hum Genet 76, 1-8 (2012). mtDNA haplogroup T coronary artery disease Austria B. Kofler et al., Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study. BMC Med Genet 10, 35 (2009), 10.1186/1471-2350-10-35. mtDNA 16189C coronary artery disease Austria E. E. Mueller et al., The mitochondrial T16189C polymorphism is associated with coronary artery disease in Middle European populations. PLoS One 6, e16455 (2011), 10.1371/journal.pone.0016455. mtDNA haplogroup H early-onset myocardial Spain M. Palacin et al., Mitochondrial DNA and TFAM gene variation in early-onset infarction myocardial infarction: evidence for an association to haplogroup H. Mitochondrion 11, 176-181 (2011). mtDNA haplogroups A, M7a coronary atherosclerosis Japan M. Sawabe et al., Mitochondrial haplogroups A and M7a confer a genetic risk for coronary atherosclerosis in the Japanese elderly: an autopsy study of 1,536 patients. J Atheroscler Thromb 18, 166-175 (2011). Y chromosome haplogroup K atherosclerotic plaque Cyprus K. Voskarides, D. Hadjipanagi, L. Papazachariou, M. Griffin, A. G. Panayiotou, occurrence Evidence for contribution of the Y chromosome in atherosclerotic plaque occurrence in men. Genet Test Mol Biomarkers 18, 552-556 (2014).

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Coronary Conditions (cont.) Y chromosome haplogroup reduced risk of Cyprus K. Voskarides, D. Hadjipanagi, L. Papazachariou, M. Griffin, A. G. Panayiotou, YAP atherosclerotic plaque Evidence for contribution of the Y chromosome in atherosclerotic plaque occurrence in men. Genet Test Mol Biomarkers 18, 552-556 (2014).

Y chromosome haplogroups no association with Poland G. Kostrzewa, G. Broda, M. Konarzewska, P. Krajewki, R. Płoski. Genetic cardiovascular risk polymorphism of human Y chromosome and risk factors for cardiovascular diseases: a study in WOBASZ cohort. PLoS ONE 8, e68155 (2013), doi:10.1371/journal.pone.0068155. mtDNA haplogroup H hypertrophic Denmark C. M. Hagen et al., Mitochondrial haplogroups modify the risk of developing cardiomyopathy hypertrophic cardiomyopathy in a Danish population. PLoS One 8, e71904 (2013), 10.1371/journal.pone.0071904. Y chromosome haplogroups no association with Holland H. G. de Haan et al., Male-specific risk of first and recurrent venous thrombosis: a recurrent venous phylogenetic analysis of the Y chromosome. J Thromb Haemost. (2016), doi: thrombosis 10.1111/jth.13437. mtDNA haplogroup D4b reduced risk of ischemic China D. Yang et al., Mitochondrial DNA haplogroup D4b is a protective factor for ischemic stroke stroke in Chinese Han population. Mol Genet Genomics. 289, 6, 1241-6 (2014).

mtDNA haplogroup N9 facilitates neurological China B. Cai et al., Mitochondrial DNA haplogroups and short-term neurological outcomes of recovery after ischemic ischemic stroke. Sci Rep 20, 5, 9864 (2015), 10.1038/srep09864. stroke mtDNA haplogroup H subclinical carotid Russia A. Zhelankin et al., 1A.06: Mitochondrial DNA haplogroup H is associated with atherosclerosis subclinical carotid atherosclerosis in Russian population. J Hypertens 33 suppl 1:e2 (2015), 10.1097/01.hjh.0000467356.04711.5 mtDNA haplogroups J, Uk reduced risk of Denmark C. M. Hagen et al., Mitochondrial haplogroups modify the risk of developing hypertrophic hypertrophic cardiomyopathy in a Danish population. PLoS One 8, e71904 (2013), cardiomyopathy 10.1371/journal.pone.0071904. mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Type 2 Diabetes mtDNA haplogroups F, D4b type 2 diabetes Japan, Korea Y. Nishigaki, N. Fuku, M. Tanaka, Mitochondrial haplogroups associated with lifestyle- related diseases and longevity in the Japanese population. Geriatr Gerontol Int 10 Suppl 1, S221-235 (2010). mtDNA haplogroups H, H3, complications from Italy A. Achilli et al., Mitochondrial DNA backgrounds might modulate diabetes U3, V diabetes complications rather than T2DM as a whole. PLoS One 6, e21029 (2011), 10.1371/journal.pone.0021029. mtDNA haplogroup N9a reduced risk of type 2 Japan, Korea Y. Nishigaki, N. Fuku, M. Tanaka, Mitochondrial haplogroups associated with lifestyle- diabetes related diseases and longevity in the Japanese population. Geriatr Gerontol Int 10 Suppl 1, S221-235 (2010). mtDNA haplogroup J1 type 2 diabetes Europe, J. Feder et al., Parental diabetes status reveals association of mitochondrial DNA North Africa haplogroup J1 with type 2 diabetes. BMC Med Genet 10, 60 (2009), 10.1186/1471- 2350-10-60. mtDNA 16189C no association with type 2 China L. Zhong et al., Reappraising the relationship between mitochondrial DNA variant diabetes m.16189t > c and type 2 diabetes mellitus in East Asian populations. Curr Mol Med 14, 1273-1278 (2014). mtDNA 16390A type 2 diabetes Tunisia S. Hsousa, et al., Association study of mitochondrial DNA polymorphisms with type 2 diabetes in Tunisian population. Mitochondr DNA 26, 367-372 (2015).

mtDNA haplogroups M8a, N9a type 2 diabetes China Q. Niu et al., Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications. Exp Ther Med 10, 1918-1924 (2015).

mtDNA 3243G, 16189C type 2 diabetes Asia S. H. Kwak, K. S. Park, Role of mitochondrial DNA variation in the pathogenesis of diabetes mellitus. Front Biosci (Landmark Ed.) 21, 1151-1167 (2016).

mtDNA haplogroups and no association with type 2 Denmark S. Li et al., Variation and association to diabetes in 2000 full mtDNA sequences mined mutations diabetes from an exome study in a Danish population. Eur J Hum Genet 22, 1040-1045 (2014). mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Hearing Loss mtDNA haplogroup L1 noise-induced hearing loss Brazil R. S. Abreu-Silva et al., The search of a genetic basis for noise-induced hearing loss (NIHL). Ann Hum Biol 38, 210-218 (2011). mtDNA 1555G aminoglycoside-induced, China Y. Bai et al., A six-generation Chinese family in haplogroup B4C1C exhibits high non-syndromic hearing penetrance of 1555A > G-induced hearing Loss. BMC Med Genet 11, 129 (2010), loss 10.1186/1471-2350-11-129. mtDNA 1555G non-syndromic Morocco H. Nahili et al., Prevalence of the mitochondrial A 1555G mutation in Moroccan sensorineural hearing loss patients with non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol 74, 1071-1074 (2010). mtDNA 1555G aminoglycoside-induced, China J. Lu et al., Mitochondrial haplotypes may modulate the phenotypic manifestation of the non-syndromic hearing deafness-associated 12S rRNA 1555A>G mutation. Mitochondrion 10, 69-81 (2010). loss mtDNA 1555G, haplogroup B higher risk, penetrance, & China J. Lu et al., Mitochondrial haplotypes may modulate the phenotypic manifestation of the expressivity of hearing deafness-associated 12S rRNA 1555A>G mutation. Mitochondrion 10, 69-81 (2010). loss mtDNA 1555G, 961G non-syndromic Italy V. Guaran et al., Association between idiopathic hearing loss and mitochondrial DNA sensorineural hearing loss mutations: a study on 169 hearing-impaired subjects. Int J Mol Med 32, 785-794 (2013). mtDNA 1555G, 3243G, non-syndromic hearing Japan T. Yano et al., Frequency of mitochondrial mutations in non-syndromic hearing loss as 3595G, 6204G loss well as possibly responsible variants found by whole mitochondrial genome screening. J Hum Genet 59, 100-106 (2014). mtDNA 1222G non-syndromic China Q. Wei et al., Genetic mutations of GJB2 and mitochondrial 12S rRNA in sensorineural hearing loss nonsyndromic hearing loss in Jiangsu Province of China. J Transl Med 11, 163 (2013). mtDNA 1555G, haplogroup B aminoglycoside-induced, China Z. Ying et al., Mitochondrial haplogroup B increases the risk for hearing loss among the non-syndromic hearing Eastern Asian pedigrees carrying 12S rRNA 1555A>G mutation. Protein Cell 6, 844- loss 848 (2015).

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Hearing Loss (cont.) mtDNA haplogroups D4a, aminoglycoside-induced, China X. Tang et al., Mitochondrial tRNA(Ser(UCN)) variants in 2651 Han Chinese subjects M22, H2 non-syndromic hearing with hearing loss. Mitochondrion 23, 17-24 (2015). loss mtDNA haplogroups and no association with age- Belgium S. Bonneaux et al., Inherited mitochondrial variants are not a major cause of age-related mutations related hearing impairment hearing impairment in the European population. Mitochondrion 11, 729-734 (2011). mtDNA 7505C non-syndromic hearing China X. Tang et al., Maternally inherited hearing loss is associated with the novel loss mitochondrial tRNA Ser(UCN) 7505T>C mutation in a Han Chinese family. Mol Genet Metab 100, 57-64 (2010).

Hypertension mtDNA 4291C hypertension, hypercho- USA F. H. Wilson et al., A cluster of metabolic defects caused by mutation in a lesterolemia, mitochondrial tRNA. Science 306, 1190-1194 (2004). hypomagnesemia mtDNA 4401G hypertension China R. Li et al., Failures in mitochondrial tRNAMet and tRNAGln metabolism caused by the novel 4401A>G mutation are involved in essential hypertension in a Han Chinese Family. Hypertension 54, 329-337 (2009). mtDNA 4435G hypertension China Z. Lu et al., The tRNAMet 4435A>G mutation in the mitochondrial haplogroup G2a1 is responsible for maternally inherited hypertension in a Chinese pedigree. Eur J Hum Genet 19, 1181-1186 (2011). mtDNA 4295G hypertension China Z. Li, Y. Liu, L. Yang, S. Wang, M. X. Guan, Maternally inherited hypertension is associated with the mitochondrial tRNAIle A4295G mutation in a Chinese family. Biochem Biophys Res Commun 367, 906-911 (2008). mtDNA haplogroup H not associated with Russia A. Zhelankin et al., 1A.06: Mitochondrial DNA haplogroup H is associated with hypertension subclinical carotid atherosclerosis in Russian population. J Hypertens 33 suppl 1:e2 (2015), 10.1097/01.hjh.0000467356.04711.5 B. mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Hypertension (cont.) mtDNA haplogroups M, HV, pulmonary arterial USA S. Farha et al., Mitochondrial Haplogroups and Risk of Pulmonary Arterial JT, UK hypertension Hypertension. PLoS One 11, e0156042 (2016). mtDNA haplogroup L reduced risk of pulmonary USA S. Farha et al., Mitochondrial Haplogroups and Risk of Pulmonary Arterial arterial hypertension Hypertension. PLoS One 11, e0156042 (2016). mtDNA 4263G hypertension China S. Wang et al., Maternally inherited essential hypertension is associated with the novel 4263A4G mutation in the mitochondrial tRNAIle gene in a large Han Chinese family. Circ Res 108, 862-870 (2011).

Infertility Y chromosome haplogroup K male infertility Latvia A. Puzuka et al., Y chromosome—a tool in infertility studies of Latvian population. Russian Journal of Genetics 47, 347-353 (2011). Y chromosome haplogroups F, male infertility China J. Ran et al., Association study between Y-chromosome haplogroups and susceptibility K, P, N1 to spermatogenic impairment in Han People from southwest China. Genet Mol Res 12, 59-66 (2013).

Bone Disease mtDNA haplogroup U increased severity of knee Spain I. Rego-Perez, M. Fernandez-Moreno, C. Fernandez-Lopez, J. Arenas, F. Blanco, osteoarthritis Mitochondrial DNA haplogroups: role in the prevalence and severity of knee osteoarthritis. Arthritis Rheum 58, 2387-2396 (2008). mtDNA haplogroup J reduced risk of knee Spain I. Rego-Perez, M. Fernandez-Moreno, C. Fernandez-Lopez, J. Arenas, F. Blanco, osteoarthritis Mitochondrial DNA haplogroups: role in the prevalence and severity of knee osteoarthritis. Arthritis Rheum 58, 2387-2396 (2008). mtDNA haplogroup J reduced risk of hip Spain I. Rego, et al., Role of european mitochondrial DNA haplogroups in the prevalence of osteoarthritis hip osteoarthritis in Galicia, Northern Spain. Ann Rheum Dis 69, 210-213 (2010). mtDNA haplogroup X lower hip bone mineral USA Y. Guo et al., Mitochondria-wide association study of common variants in osteoporosis. density (osteoporosis) Ann Hum Genet 75, 569-574 (2011). mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Bone Disease (cont.) mtDNA 4823C lower hip bone mineral USA Y. Guo et al., Mitochondria-wide association study of common variants in osteoporosis. density (osteoporosis) Ann Hum Genet 75, 569-574 (2011). mtDNA haplogroup G knee osteoarthritis China H. Fang et al., Role of mtDNA haplogroups in the prevalence of knee osteoarthritis in a southern Chinese population. Int J Mol Sci 15, 2646-2659 (2014). mtDNA haplogroups B, B4 reduced risk of knee China H. Fang et al., Role of mtDNA haplogroups in the prevalence of knee osteoarthritis in a osteoarthritis southern Chinese population. Int J Mol Sci 15, 2646-2659 (2014). mtDNA haplogroups J, T reduced risk of UK, Spain A. Soto-Hermida et al., mtDNA haplogroups and osteoarthritis in different geographic osteoarthritis populations. Mitochondrion 15, 18-23 (2014). mtDNA haplogroups J, TJ osteoarthritis Spain J. M. Shen, et al., Role of mtDNA haplogroups in the prevalence of osteoarthritis in different geographic populations: a meta-analysis. PLoS One 9, e108896 (2014). doi:10.1371/journal.pone.0108896 mtDNA haplogroup TJ slower osteoarthritis Spain A. Soto-Hermida et al., Mitochondrial DNA haplogroups modulate the radiographic progression progression of Spanish patients with osteoarthritis. Rheumatol Int 35, 337-344 (2015). mtDNA haplogroup H more joint surgery for Spain A. Soto-Hermida et al., Mitochondrial DNA haplogroups modulate the radiographic osteoarthritis progression of Spanish patients with osteoarthritis. Rheumatol Int 35, 337-344 (2015). mtDNA haplogroups no association with UK G. Hudson et al., No evidence of an association between mitochondrial DNA variants osteoarthritis and osteoarthritis in 7393 cases and 5122 controls. Ann Rheum Dis 72, 136-139 (2013).

AIDS/HIV Antiviral Therapy Complications mtDNA haplogroups U5a, J accelerated AIDS USA S. L. Hendrickson et al., Mitochondrial DNA haplogroups influence AIDS progression. progression AIDS 22, 2429-2439 (2008). mtDNA haplogroups I, W, X, delayed onset of AIDS USA S. L. Hendrickson et al., Mitochondrial DNA haplogroups influence AIDS progression. H3 AIDS 22, 2429-2439 (2008).

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location AIDS/HIV Antiviral Therapy Complications (cont.) mtDNA haplogroup Uk reduced risk of AIDS USA S. L. Hendrickson et al., Mitochondrial DNA haplogroups influence AIDS progression. AIDS 22, 2429-2439 (2008). mtDNA haplogroup L1c peripheral neuropathy USA J. A. Canter et al., African mitochondrial DNA subhaplogroups and peripheral during HIV antiretroviral neuropathy during antiretroviral therapy. J Infect Dis 201, 1703-1707 (2010). therapy mtDNA haplogroup L2 slower CD4 T-cell USA B. J. Grady et al., Mitochondrial genomics and CD4 T-cell count recovery after recovery during HIV antiretroviral therapy initiation in AIDS clinical trials group study 384. J Acquir antiretroviral therapy Immune Defic Syndr 58, 363-370 (2011). mtDNA haplogroup I lipoatrophy during HIV USA T. Hulgan et al., European mitochondrial DNA haplogroups and metabolic changes antiretroviral therapy during antiretroviral therapy in AIDS Clinical Trials Group Study A5142. AIDS 25, 37- 47 (2011). mtDNA haplogroup J reduced risk of USA S. L. Hendrickson et al., Genetic variants in nuclear-encoded mitochondrial genes neuroretinal disorder influence AIDS progression. PLoS One 5, e12862 (2010), during HIV antiretroviral 10.1371/journal.pone.0012862. therapy mtDNA haplogroup L2 slower CD4 T-cell USA B. Aissani et al., Mitochondrial DNA variation and virologic and immunological HIV recovery during HIV outcomes in African Americans. AIDS 28, 1871-1878 (2014). antiretroviral therapy mtDNA haplogroups J, T slower CD4 T-cell Spain M. Guzman-Fulgencio et al., European mitochondrial haplogroups are associated with recovery during HIV CD4+ T cell recovery in HIV-infected patients on combination antiretroviral therapy. J antiretroviral therapy Antimicrob Chemother 68, 2349-2357 (2013). European mtDNA haplogroups not associated with Spain M. Guzmán-Fulgencio et al., European mitochondrial haplogroups are not associated hepatitis C virus treatment with hepatitis C virus (HCV) treatment response in HIV/HCV-coinfected patients. HIV response Med 15, 425-430 (2014). mtDNA haplogroup A susceptibility to AIDS China H. W. Wang, et al., Mitochondrial DNA Haplogroup A may confer a genetic susceptibility to AIDS group from Southwest China.Mitochondrial DNA A DNA Mapp Seq Anal 27, 2221-2224 (2016). mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location AIDS/HIV Antiviral Therapy Complications (cont.) mtDNA haplogroup B less neurocognitive USA T. Hulgan et al., Mitochondrial DNA Haplogroups and Neurocognitive Impairment impairment during HIV During HIV Infection. Clin Infect Dis 61, 1476-1484 (2015). antiretroviral therapy mtDNA haplogroup H faster CD4 T-cell recovery Spain M. Guzman-Fulgencio et al., European mitochondrial haplogroups are associated with during HIV antiretroviral CD4+ T cell recovery in HIV-infected patients on combination antiretroviral therapy. J therapy Antimicrob Chemother 68, 2349-2357 (2013).

Neurodegenerative Conditions/Treatment Response mtDNA haplogroup H (7028C) earlier onset of Germany L. Arning et al., Mitochondrial haplogroup H correlates with ATP levels and age at Huntington's disease onset in Huntington disease. J Mol Med (Berl) 88, 431-436 (2010). mtDNA haplogroup H (7028C) late onset Alzheimer's Spain E. Coto et al., Late-onset Alzheimer's disease is associated with mitochondrial DNA disease 7028C/haplogroup H and D310 poly-C tract heteroplasmy. Neurogenetics 12, 345-346 (2011). mtDNA haplogroups J1c, J2, reduced risk of Parkinson's Poland K. Gaweda-Walerych et al., Mitochondrial transcription factor A variants and the risk U4, U5a1, K disease of Parkinson's disease. Neurosci Lett 469, 24-29 (2010). mtDNA haplogroup H Alzheimer's and Spain A. Gomez-Duran et al., Unmasking the causes of multifactorial disorders: OXPHOS Parkinson's diseases differences between mitochondrial haplogroups. Hum Mol Genet 19, 3343-3353 (2010). mtDNA haplogroup Uk reduced risk of Spain A. Gomez-Duran et al., Unmasking the causes of multifactorial disorders: OXPHOS Alzheimer's and differences between mitochondrial haplogroups. Hum Mol Genet 19, 3343-3353 (2010). Parkinson's disease mtDNA haplogroup Uk Alzheimer's disease USA, Canada A. Lakatos et al., Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort. Neurobiol Aging 31, 1355-1363 (2010).

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Neurodegenerative Conditions/Treatment Response (cont.) mtDNA haplogroups no association with N.A. M. Mancuso, V. Calsolaro, D. Orsucci, G. Siciliano, L. Murri, Is there a primary role of Alzheimer's disease the mitochondrial genome in Alzheimer's disease? J Bioenerg Biomembr 41, 411-416 (2009). mtDNA haplogroup E1 Parkinson's disease Guam D. M. Reiff et al., Inherited and somatic mitochondrial DNA mutations in Guam amyotrophic lateral sclerosis and parkinsonism-dementia. Neurol Sci 32, 883-892 (2011). mtDNA haplogroup E2 reduced risk of Parkinson's Guam D. M. Reiff et al., Inherited and somatic mitochondrial DNA mutations in Guam disease amyotrophic lateral sclerosis and parkinsonism-dementia. Neurol Sci 32, 883-892 (2011). mtDNA haplogroup H5 Alzheimer's disease Italy A. Santoro et al., Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease. PLoS One 5, e12037 (2010), 10.1371/journal.pone.0012037. mtDNA haplogroups no association with USA D. K. Simon et al., Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease Parkinson's disease. BMC Med Genet 11, 53 (2010), 10.1186/1471-2350-11-53. mtDNA haplogroup H Parkinson's disease UK G. Hudson et al., Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology 80, 2042-2048 (2013). mtDNA haplogroups J, K, T reduced risk of Parkinson's UK G. Hudson et al., Two-stage association study and meta-analysis of mitochondrial DNA disease variants in Parkinson disease. Neurology 80, 2042-2048 (2013). mtDNA haplogroup D Parkinson's disease China Y. F. Chen et al., Mitochondrial DNA Haplogroups and the Risk of Sporadic Parkinson's Disease in Han Chinese. Chin Med J (Engl) 128, 1748-1754 (2015).

mtDNA haplogroup B reduced risk of Parkinson's China Y. F. Chen et al., Mitochondrial DNA Haplogroups and the Risk of Sporadic disease Parkinson's Disease in Han Chinese. Chin Med J (Engl) 128, 1748-1754 (2015).

mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Neurodegenerative Conditions/Treatment Response (cont.) mtDNA haplogroup B5 Alzheimer's disease China R. Bi et al., Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese. Neurobiol Aging 36, 1604.e7-16 (2015).

mtDNA haplogroup L1 Alzheimer's disease USA G. J. Tranah et al., Mitochondrial DNA sequence associations with dementia and amyloid-beta in elderly African Americans. Neurobiol Aging 35, 442 e441-448 (2014).

Opthalmic Diseases/Conditions mtDNA 10609C, 10663C Leber's hereditary optic Kuwait R. Behbehani et al., ND4L gene concurrent 10609T > C and 10663T > C mutations are neuropathy associated with Leber's hereditary optic neuropathy in a large pedigree from Kuwait. Brit J Ophthalmol 98, 826-831 (2014). mtDNA haplogroups H, R keratoconus Saudi Arabia K.K. Abu-Amero et al., Association of mitochondrial haplogroups H and R with keratoconus in Saudi Arabian patients. Invest Ophth Vis Sci 55, 2827-2831 (2014). mtDNA haplogroup T increased risk of diabetic Austria B. Kofler et al., Mitochondrial DNA haplogroup T is associated with coronary artery retinopathy disease and diabetic retinopathy: a case control study. BMC Med Genet 10: 35 (2009), 10.1186/1471-2350-10-35. mtDNA 14484C Leber's hereditary optic Various T. M. Bosley, K. K. Abu-Amero, Assessing mitochondrial DNA nucleotide changes in neuropathy spontaneous optic neuropathies. Ophthalmic Genet 31, 163-172 (2010); N.A. Khan et al., Haplogroup heterogeneity of LHON patients carrying the m.14484T > C mutation in India. Invest Ophth Vis Sci 54, 3999-4005 (2013).

mtDNA haplogroup T2 age-related macular USA, J. P. SanGiovanni et al., Mitochondrial DNA variants of respiratory complex I that degeneration Australia uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One 4, e5508 (2009), 10.1371/journal.pone.0005508. mtDNA haplogroup L primary open-angle Saudi Arabia K. K. Abu-Amero et al., Mitochondrial DNA lineages of African origin confer glaucoma susceptibility to primary open-angle glaucoma in Saudi patients. Mol Vis 17, 1468-1472 (2011). mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Opthalmic Diseases/Conditions (cont.) mtDNA haplogroup N1 reduced risk of primary Saudi Arabia K. K. Abu-Amero et al., Mitochondrial DNA lineages of African origin confer open-angle glaucoma susceptibility to primary open-angle glaucoma in Saudi patients. Mol Vis 17, 1468-1472 (2011). mtDNA haplogroups L2, T pseudoexfoliation Saudi Arabia K. K. Abu-Amero et al., Eurasian and Sub-Saharan African mitochondrial DNA glaucoma haplogroup influences pseudoexfoliation glaucoma development in Saudi patients. Mol Vis 17, 543-547 (2011). mtDNA haplogroup N1 reduced risk of Saudi Arabia K. K. Abu-Amero et al., Eurasian and Sub-Saharan African mitochondrial DNA pseudoexfoliation haplogroup influences pseudoexfoliation glaucoma development in Saudi patients. Mol glaucoma Vis 17, 543-547 (2011). mtDNA 11778A Leber's hereditary optic Various T. M. Bosley, K. K. Abu-Amero, Assessing mitochondrial DNA nucleotide changes in neuropathy spontaneous optic neuropathies. Ophthalmic Genet 31, 163-172 (2010). mtDNA 3460A Leber's hereditary optic Various T. M. Bosley, K. K. Abu-Amero, Assessing mitochondrial DNA nucleotide changes in neuropathy spontaneous optic neuropathies. Ophthalmic Genet 31, 163-172 (2010). mtDNA haplogroup B5a1 Leber's hereditary optic Thailand S. Kaewsutthi et al., Mitochondrial haplogroup background may influence Southeast neuropathy Asian G11778A Leber hereditary optic neuropathy. Invest Ophth Vis Sci 52, 4742-4748 (2011). mtDNA haplogroup F reduced risk of Leber's Thailand S. Kaewsutthi et al., Mitochondrial haplogroup background may influence Southeast hereditary optic Asian G11778A Leber hereditary optic neuropathy. Invest Ophth Vis Sci 52, 4742-4748 neuropathy (2011). mtDNA haplogroup U reduced risk of exfoliation Germany C. Wolf et al., Mitochondrial haplogroup U is associated with a reduced risk to develop glaucoma exfoliation glaucoma in the German population. BMC Genet 11, 8 (2010), 10.1186/1471-2156-11-8. mtDNA haplogroups A2, C later onset/reduced impact Chile P. Romero et al., Pan-American mDNA haplogroups in Chilean patients with Leber's of Leber's hereditary optic hereditary optic neuropathy. Mol Vis 14, 334-40 (2014).

neuropathy mtDNA or Y Chromosome Proposed Association (or Study Reference Variant Lack of Association) Location Opthalmic Diseases/Conditions (cont.) mtDNA 14502C, 11778A Leber's hereditary optic China P. Jiang et al., Biochemical evidence for a mitochondrial genetic modifier in the neuropathy phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation. Hum Mol Genet Jul 17. pii: ddw199 (2016). mtDNA 3635A, 14502C Leber's hereditary optic China X. Jin et al., Leber's Hereditary Optic Neuropathy is Associated with Compound neuropathy Primary Mutations of Mitochondrial ND1 m.3635G > A and ND6 m.14502 T > C. Ophthalmic Genet 36, 291-298 (2015). mtDNA 16111, 16362, 16319, age-related macular USA N. A. Resrepo, et al., Mitochondrial variation and the risk of age-related macular 1736, 12007 degeneration degeneration across diverse populations. Pac Symp Biocomput. 243-54 (2015).

mtDNA haplogroups J, T, U age-related macular USA M. C. Kenney et al., Mitochondrial DNA haplogroups confer differences in risk for age- degeneration related macular degeneration: a case control study. BMC Med Genet 14 (2014), 10.1186/1471-2350-14-4.